Structure–Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM‐254890, Targeting the G_q Protein

Abstract

Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the G subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective G inhibitory activity. This provides pertinent information for the understanding of the G inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues.

Cell‐permeable high‐affinity tracers for Gq proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors

“…MD simulation studies of Gα q protein in complex with FR and YM, respectively, indicated that the kinetic differences are largely contributed by the isopropyl (R 2 in Figure b) interaction with Phe75 in the binding pocket. The new tracers will allow to study binding kinetics of other compounds that bind to the same site, for example, novel analogues and derivatives of YM and FR, that are accessible by chemical synthesis (Rensing, Uppal, Blumer, & Moeller, ; Xiong et al, ; Zhang et al, ), and by biotechnological approaches (Crüsemann et al, ; Taniguchi et al, ). The new tracers will help to design and develop G q inhibitors with specific, desired kinetic profiles.…”

“…A few analogues of FR have also been isolated, however, in tiny amounts (Crüsemann et al, ; Reher et al, ). Recently, the total syntheses of 1 and 2 and some analogues were described, but they represent labour‐intensive procedures providing only small amounts of the products; all of the synthesized analogues showed moderate potency or were inactive (Xiong et al, ; Zhang et al, ). In functional studies, FR and YM were found to be similarly potent and selective Gα q/11 protein inhibitors.…”

Recent achievements in developing selective Gq inhibitors

“…b, Inhibition of the adenosine diphosphate (ADP)‐induced platelet aggregation in human platelet‐rich plasma . c, d, and e, Inhibition of carbachol‐induced inositol monophosphate (IP 1 ) production in Chinese hamster ovary (CHO) cells that stably express the M 1 muscarinic receptor in different papers: (c) from Xiong et al, (d) from Zhang et al and Xiong et al, and (e) from Reher et al Equipotent analogs are highlighted (pink). The chemical structures were determined by mass spectrometry, one‐ and two‐dimensional nuclear magnetic resonance (NMR) spectrum analysis, chiral high‐performance liquid chromatography (HPLC), Marfey's analysis, high‐resolution mass spectroscopy (HRMS), infrared spectroscopy (IR), and optical rotation.…”

“…d, Inhibition of the adenosine diphosphate (ADP)‐induced platelet aggregation in vitro . e, f, g, h, i, and j, Inhibition of carbachol‐induced IP 1 production in Chinese hamster ovary (CHO) cells that stably express the M 1 muscarinic receptor in different papers: (e) from Xiong et al, (f) from Xiong et al, (g) from Zhang et al, (h) from Zhang et al, (i) from Reher et al, and (j) from Zhang…”

“…Subsequently, the versatility of the synthetic methodology was demonstrated by the synthesis of more than 30 structurally and stereochemically diverse analogs, which allowed for systematic structure‐activity relationship (SAR) studies of YM‐254890 that focus on the modification of key structural elements such as (i) the N ‐MeDha residue (YM‐385780 ( 7 ), YM‐385781 ( 8 ), YM‐19 to YM‐25 ( 9 ‐ 15 ), Figure ), (ii) the backbone (YM‐1 to YM‐5 ( 16 ‐ 20 ), Figure ), (iii) key β‐HyLeu moieties (YM‐6 to YM‐9 ( 21 ‐ 24 ), YM‐10 ( 2 , also known as YM‐254891), Figures a and ), (iv) side‐chains of N ‐MeAla and Ala (YM‐11 to YM‐18 ( 25‐32 ), Figure ), and (v) side chains of Thr and the N ‐acyl group of β‐HyLeu‐1 (YM‐26 to YM‐30 ( 33 ‐ 37 ), Figure ) . These analogs have highlighted how the bulkiness, stereochemistry and electron density of each amino acid in YM‐254890 influence G q inhibitory potency and selectivity.…”